Premature newborns are at increased risk of pulmonary infection due to the immaturity of inflammatory cells including the alveolar macrophage (AM). The AM is the first line of defense against infection in the lung. Glutathione, (GSH) a major antioxidant in the lung, is required by the AM to maintain redox potential and optimize intracellular functioning. Levels of systemic and alveolar GSH are deficient in the premature newborn, placing the lung at increased risk for oxidant injury and cellular dysfunction. Chronic alcohol (ETOH) exposure to adults also increases systemic oxidative stress and impairs the immune function of the AM. ETOH consumption has increased significantly in women of childbearing age and remains a significant health problem in our society. The fetus exposed to ETOH in utero is at risk for systemic oxidant stress, as evidenced by decreased systemic and hepatic GSH, and increased markers of reactive oxygen species. We postulate that the pulmonary GSH deficiency caused by prematurity is exacerbated when superimposed on oxidant stress, such as that caused by in utero ETOH exposure. Decreased GSH in the lung decreases GSH availability for the resident AM, thereby contributing to impaired AM function. In a guinea pig model af fetal ETOH exposure, preliminary studies showed that ETOH decreased GSH in the fetal epithelial lining fluid, resulting in decreased AM GSH compared to gestationally matched controls. The ETOH-exposed AM demonstrated impaired functions, increased oxidative stress, and accentuated apoptosis. This is clinically relevant because it suggested that the functions of the immature AM may be further impaired if the chronic oxidative stress of ETOH exposure is superimposed on premature delivery. The addition of GSH precursors in vivo or in vitro partially restored AM function and reduced apoptosis of ETOH-exposed AM. We hypothesize that chronic in utero ETOH exposure depletes alveolar GSH and the resultant chronic oxidative stress impairs AM functions such as phagocytosis and viability. Furthermore, we hypothesize GSH supplements will decrease oxidative stress in the ETOH-impaired AM and improve functions such as phagocytosis and viability. We propose Four Specific Aims to determine: 1) if in utero ETOH exposure impairs AM function by increasing oxidative stress and AM apoptosis across gestation, 2) if cytokine stimulation further impairs function and increases apoptosis of the developing ETOH-exposed AM, 3) if in vitro GSH supplementation restores ETOH-exposed AM functions and reduces apoptosis, and 4) if in vivo GSH precursors, administered during ETOH ingestion, protect the developing AM from ETOH induced dysfunction, oxidative stress and apoptosis. Results from this proposal will identify novel effects of fetal ETOH exposure on the developing AM within the lung, providing new insight on potential clinical strategies to optimize the function of these cells in the premature newborn.